Am J Physiol Regul Integr Comp Physiol. Author manuscript; available in PMC May 1, 2007.Published in final edited form as:Am J Physiol Regul Integr Comp Physiol. May 2006; 290(5): R1153R1167.doi:10.1152/ajpregu.00402.2005PMCID:PMC1578723NIHMSID:NIHMS12197Renal Autoregulation: New Perspectives Regarding the Protective and Regulatory Roles of the Underlying MechanismsRodger Loutzenhiser,1Karen Griffin,2Geoffrey Williamson,3andAnil Bidani2Author informationCopyright and License informationThe publisher's final edited version of this article is available atAm J Physiol Regul Integr Comp PhysiolSee other articles in PMC thatcitethe published article.Go to:AbstractWhen the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least in regard to the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure, and the accruing evidence that when this response is impaired the primary consequence is not a disturbed volume homeostasis, but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms are capable of achieving volume regulation despite considerable fluctuations in distal delivery and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms may exist to maintain ambient levels of RBF and GFR within normal range despite chronic alterations in BP and severely impaired acute responses to pressure. Finally the implications of this new perspective on the divergent roles of the renal myogenic response to pressure versus the TGF response to changes in distal delivery are considered and it is proposed that, in addition to TGF-induced vasoconstrictor responses, vasodepressor responses to reduced distal delivery may play a more critical role in modulating afferent arteriolar reactivity, in order to integrate the regulatory and protective functions of the renal microvasculature.Keywords:Renal Microcirculation, Afferent Arteriole, Myogenic, Tubuloglomerular Feedback, Renal AutoregulationGo to:IntroductionOne of the most striking characteristics of the renal circulation is the ability of the kidney to maintain a constant renal blood flow (RBF) and glomerular filtration rate (GFR) as renal perfusion pressure is altered. The dual regulation of both RBF and GFR is achieved by proportionate changes in the preglomerular resistance and is believed to be mediated by two mechanisms, tubuloglomerular feedback (TGF) and the renal myogenic response. TGF involves a flow-dependent signal that is sensed at the macula densa, and alters tone in the adjacent segment of the afferent arteriole via a mechanism that remains controversial, but likely involves adenosine and/or ATP (30,80,144). The myogenic response involves a direct vasoconstriction of the afferent arteriole when this vessel is presented with an increase in transmural pressure. The current view is that these two mechanisms act in concert and that their primary role is to stabilize renal function by preventing pressure-induced fluctuations in RBF, GFR and the delivery of filtrate to the distal tubule (distal delivery).Over the last two decades, evidence has accrued to indicate that this autoregulatory response plays a concurrent role in protecting the kidney from hypertensive injury (14,15). This view is based on the strong link between autoregulatory capacity and susceptibility to hypertensive injury. In the presence of intact autoregulation, minimal injury is observed despite substantial hypertension. However, when blood pressure (BP) is elevated beyond the upper limit of normal autoregulatory capacity, renal damage develops rapidly. Conversely, if autoregulatory capacity is diminished, susceptibility to hypertensive renal damage is greatly enhanced and injury is observed with even moderate hypertension. Nevertheless, the primary function of the renal vascular responses to pressure, and of the myogenic and TGF mechanisms, is believed to be regulatory, as reflected in the very term autoregulation. Thus renal protection is lost when renal autoregulation fails. However, as discussed below, the requirements for maintaining a constant GFR and for protecting the glomerulus from hypertensive injury differ, even though both involve a regulation of glomerular capillary pressure (PGC). Moreover, the myogenic response and TGF system clearly sense different signals and, therefore, may play distinct roles in protection and regulation. This review presents the authors' perspective on the role of vascular responses to pressure in regulating renal function and in protecting the kidney against the adverse effects of elevated systemic BP.Go to:Historical PerspectivesRenal autoregulation may have first been described by Rein in 1931 (125). However as early as 1902, Bayliss observed that the renal vasculature exhibits a profound vasoconstriction when the kidney was subjected to elevated pressure (12). Bayliss viewed the renal response as an example of the myogenic response of vascular beds. In regard to the purpose of this general response, he suggested thatThe peripheral powers of reaction possessed by the arteries is of such a nature as to provide as far as possible for the maintenance of a constant flow of blood through the tissues supplied by them, whatever may be the height of the general blood-pressure(12). The concept that renal vascular responses to pressure might also serve to regulate function in the kidney was further advanced by the observation of Forster and Maes in 1947 (49) that not only RBF but also GFR remained constant with acute elevations in BP. From the outset, it was recognized that the dual regulation of GFR and RBF could only be achieved if pressure-induced vasoconstriction was restricted to preglomerular resistance vessels.It was generally accepted that, in the kidney, the need for volume preservation required that the capacity of the tubules to reabsorb the filtrate not be overwhelmed by excessive glomerular filtration rates. Specifically, the delivery of filtrate to the distal segment which has a more limited reabsorptive capacity needed to be precisely regulated. The unique anatomical relationship between the early distal nephron and its glomerular vascular pole was recognized by Goormaghtigh to provide a potential site for such regulation (53). Thus in the vast majority of mammalian nephrons, the early distal tubule makes direct contact with the vascular pole of its originating glomerulus. The early observations of Hrsing that inhibition of proximal fluid reabsorption decreased both GFR and RBF, led to his suggestion that increased filling of the distal tubule might evoke signaling via the macula densa to regulate vascular resistance (68). The subsequent demonstrations that alterations in the composition of the fluid presented to this early distal site caused reductions in the up-stream proximal stop-flow pressure (154) and that increased early distal tubular flow reduced the GFR of the affected nephron (136) established the presence of such a tubulo-glomerular feedback coupling distal filtrate delivery to preglomerular vascular responses. These observations supported the hypothesis, first proposed in 1963 (64,152), that the autoregulation of GFR and RBF involved a unique mechanism in the kidney whereby preglomerular vasoconstriction was triggered by increased distal delivery. This concept was consistent with the prevailing view that, in addition to a general myogenic response (e.g.,7,51), the differing physiologic and metabolic requirements of tissues needed to be achieved by organ-specific vascular regulatory mechanisms. Subsequent approaches, including mathematical modeling, led to the consensus that both TGF and myogenic vasoconstriction are essential for normal autoregulation (8,74,108,116), though their relative contributions remain controversial. Thus the current view is that when BP is elevated, these two mechanism act in concert to achieve a precise regulation of GFR and RBF. The underlying assumption throughout has been that this response reflects a phenomenon whose primary purpose is to insulate renal sodium and volume regulation from fluctuations in BP (e.g.,75,153,114).During this same period, Wilson and Byrom conducted their pioneering investigations into the pathogenesis of target organ damage seen in the 2 kidney/1 clip model of hypertension (2K/1C) and the involvement of autoregulatory or myogenic mechanisms (171,172). Based on the local vasospasm observed in the cerebral vasculature using the cranial window approach, it was initially thought that an exaggerated myogenic vasoconstriction and tissue ischemia led to the manifestation of hypertensive encephalopathy (28). However, subsequent studies by these and other investigators indicated that an overwhelming of the myogenic capacity in some vascular segments by excessive BP led to focal vasodilatation, increased wall tension and, ultimately, hypertensive cerebral vascular injury (reviewed in27,50). Similar mechanisms were postulated for the renal injury seen in this hypertensive model. Studies in the uninephrectomized deoxycorticosterone acetate (DOCA)/salt model of malignant nephrosclerosis by Hill and Heptinstall confirmed the enhanced susceptibility of a dilated renal vascular bed to hypertensive injury (72). These investigators additionally suggested that the severity of such damage may depend not only on the severity of the hypertension but also on the renal autoregulatory or myogenic capacity. The importance of local myogenic mechanisms in protecting against hypertensive injury was formally recognized in the concept proposed in 1972 that hypertensive encephalopathy may develop only when BPs exceed the upper limit of cerebral blood flow autoregulation (94). A great deal of experimental and clinical evidence has since been obtained in support of the concept (86,93). Moreover, although the concept was initially proposed in the context of target organ damage observed with severe or malignant hypertension, an association between preglomerular vasodilatation, increased PGCand progressive glomerulosclerosis even with moderate hypertension, was subsequently recognized in chronic kidney disease (CKD) models (9,10,77,118). The direct demonstration that, in addition to being vasodilated, the preglomerular vasculature of the 5/6 renal ablation model of CKD also exhibits impaired renal autoregulation provided a potential explanation for the greatly enhanced glomerular susceptibility to hypertensive injury seen in this model (21).Collectively, such observations suggest that the same mechanisms responsible for renal autoregulation play a critical role in protecting the kidney from the damaging effects of hypertension. Since PGCis a primary determinant of GFR and an elevation in PGCis thought to be an initiating event in the sequence leading to glomerular injury, renal protection might be viewed as simply as an ancillary consequence of the regulation of GFR. Indeed, despite the clear linkage of the loss of autoregulatory capacity and glomerular injury, the primary importance of the regulatory role of renal autoregulation and its requirement for volume homeostasis has remained a cornerstone of renal physiology.Go to:BP Variability and the Requirements for Protection versus RegulationA fundamental consideration in regard to both the regulatory and the protective functions of the renal vasculature is the fact that BP spontaneously fluctuates at multiple frequencies. This is illustrated infigure 1, which depicts the BP power spectrum of the conscious rat. Because the amplitude of the BP fluctuation varies with frequency, the BP power (energy/unit time, proportional to the square of the amplitude) is also a function of frequency. In general, slow events exhibit larger amplitudes than more rapid signals (73,103). The exception to this well-described 1/frequency relationship is the very rapid BP oscillation due to the pulse, which manifests as the power peak observed at the heart rate (6 Hz in the rat). These various frequencies summate to form the complex BP signals that are delivered to the preglomerular vasculaturein vivo. Thus the BP signals that evoke renal autoregulatory responses are always oscillatory in nature, and the kinetic attributes of TGF and the myogenic mechanism determine the frequency range over which both autoregulation and renal protection can manifest.

Figure 1Blood pressure (BP) power spectrum in the conscious rat (mean data, n=10). The BP signal is a complex wave form derived from various fluctuations that oscillate at different frequencies. BP power is proportional to the square of the amplitude of these...Dynamic autoregulatory studies, employing transfer function and frequency domain analyses, have revealed the natural frequency of the TGF mechanism in the rat to be in the range of 0.05 Hz (2,32,36,38,56,76,122,165,166). The myogenic response is much faster, with a natural frequency of 0.1-0.2 Hz in the anaesthetized rats and 0.2-0.3 Hz in conscious animals(ibid). Essentially similar data regarding the kinetics of these mechanisms have been obtained through analyses of RBF responses to step changes in BP (84,85,102,175). These natural frequencies imply that the myogenic response can prevent changes in RBF in response to BP fluctuations that occur at intervals greater than 3-4 seconds, whereas TGF responds to slower BP fluctuations, over intervals of 20 seconds or longer. Given the differences in their mechanisms, it is not surprising that these two systems exhibit markedly different response times. To elicit a TGF response, a pressure increase must be transmitted and elicit an increase in the flow rate through the thick ascending limb. This, in turn, alters the composition of the fluid presented to the macula densa, stimulating the secretion of a vasoconstrictor near the afferent arteriole, ultimately increasing preglomerular resistance. In contrast, the myogenic mechanism involves an intrinsic smooth muscle response to increased transmural pressure. The underlying mechanisms, though not fully resolved, involve depolarization, activation of voltage-gated L-type Ca+2channels and Ca+2entry triggering a rapid vasoconstriction (39).The observation that fluctuations in BP occurring faster than 0.3 Hz are accompanied by parallel RBF fluctuations, without attenuation, has been interpreted as indicating that the renal vasculature responds passively to such high frequency signals (e.g.,75). This interpretation is reasonable if one considers a regulation of function to be the primary role of this response. As illustrated infigure 1, major variations in BP occur primarily at frequencies well below 0.3 Hz and the natural frequencies of the myogenic and TGF mechanisms are sufficient to attenuate their effects on renal function. The focus on BP fluctuations occurring exclusively at low frequencies (